Differences in LDL receptor-mediated metabolism of three low density lipoprotein subfractions by human monocyte-derived macrophages: impact on the risk for atherosclerosis.

Abstract

The metabolism of three low density lipoprotein (LDL) subfractions by human monocyte-derived macrophages (HMDM) through the LDL receptor pathway was studied. The three LDL subfractions, very light LDL1, light LDL2 and heavy LDL3, were isolated from serum pools of normolipidemic subjects by density gradient ultracentrifugation. The LDL subfractions were shown to differ in molecular size and chemical composition but not in electrophoretic mobility on agarose gel. Cell specific association, cell specific degradation and stimulation of cholesteryl esterification were determined in parallel after incubation of HMDM with increasing amounts of LDL-protein of the three LDL subfractions. The experiments were repeated four times with freshly prepared LDL subfractions. Both the cell specific association and degradation increased more with increasing LDL-protein concentration for LDL1 than for LDL3 (p < 0.001). The results for LDL2 were intermediate between those for LDL1 and LDL3 and differed significantly from both (p < 0.05). For the stimulation of cholesteryl ester formation, the curves for LDL1 and LDL2 increased more with increasing LDL-protein concentration than that for LDL3 (p < 0.001); the results for LDL1 and LDL2 did not differ significantly from each other. These differences between LDL subfractions in cholesteryl esterification were independent of the cholesterol content of the LDL subfractions. The results show that LDL subfractions have different rates of LDL receptor-mediated catabolism by HMDM. As HMDM play an important role in the formation of atherosclerotic plaques, the differences between the LDL subfractions in catabolism by HMDM, may result in differences in atherogenicity between LDL subfractions isolated from normolipidemic subjects.